Cell type-specific signal transducers provide targets for either interrupting or enhancing function of specific cell subsets. CD22 is a B-lymphocyte specific membrane protein that mediates cell-cell interactions via a sialic acid dependent mechanism. Within its intracellular domain it contains several motifs that can activate signaling pathways. Gene targeting experiments have shown that CD22 may have both positive and negative effects on humoral immunity. We have developed a model system to examine CD22 signaling in a non B-cell line by introducing several signaling molecules used in B cells. With this system we have shown a role for syk in the tyrosine phosphorylation of CD22 and for the phosphatase SHP1 in deactivating CD22 signaling. To further examine the role of CD22 in the humoral response, we have transgenically expressed CD22 in mice. Those mice are currently being evaluated. A serine/threonine kinase termed GCKR that is expressed in B cells as well as many other cell types specifically activates the stress activated protein kinase pathway (SAPK). We have shown that tumor necrosis factor (TNF) is a potent inducer of GCKR activity and that the activation of GCKR by the TNF receptor accounts for the majority of TNF-induced SAPK activation. We were able to partially order the signaling pathway by showing that a dominant negative form of TRAF2 blocked TNF-induced GCKR activation and that a dominant negative MEKK1 blocked GCKR-induced SAPK activation. In contrast, GCKR is not involved in NF-(B activation, another downstream effect of TNF receptor activation. We have also shown the Bcr-Abl oncogene, found in Philadelphia chromosome positive chronic myelogenous leukemia (CML) is also a potent activator of GCKR and that interruption of GCKR activity blocks Bcr-Abl-induced SAPK activation. Bcr-Abl-induced GCKR activation was shown to be dependent on the small GTPase ras. Several CML cell lines were shown to contain high levels of GCKR activity. Thus, GCKR activation in CML cells may contribute to SAPK activation and the cellular transformation mediated by Bcr-Abl.